Diabetes mellitus (DM) is a metabolic disease characterized in that the level of glucose (blood glucose) in blood is increased, and it is a slowly progressive disease caused by genetic factors in combination with environmental factors. With the improvement in people's living standards, the number of people with diabetes is increased rapidly. According to the International Diabetes Federation, in 2012, there are about 371 million diabetic patients, and the number of diabetes patients in China is 90 million, which is the country with the largest number of patients in the world (Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care. 2004, 27, 1047-1053). Approximately 3.8 million people die from diabetes each year, and diabetes ranks thirdly as AIDS which is only after cancer and cardiovascular disease.
According to the pathogenesis, diabetes can be divided into type 1 and type 2. Type 1 diabetes is mainly due to the insufficiency of endogenous insulin secretion caused by autoimmune-damaged islet β cells; that is, absolute lack of insulin. And patients need to be treated with insulin. Type 2 diabetes is due to reduced insulin secretion or insulin resistance caused by dysfunctional islet β-cells, that is, relative lack of insulin resulting in abnormality in metabolism of sugar, protein and fat.
Clinically, diabetes is treated mainly by using a variety of oral hypoglycemic agents and insulin supplements to delay the progress of diabetes. However, these methods, sometimes, can not achieve desired therapeutic effects, and there are side effects of inducing hypoglycemia and cardiovascular disease etc., and no protective effects on injured islet cells. With the deep understanding of the pathogenesis of diabetes, it is a focus of research to find effective hypoglycemic drugs according to mechanisms of key targets in the pathogenesis.
Dipeptidyl peptidase-4 (DPP-4) has been demonstrated as an effective target for the treatment of type 2 diabetes mellitus, which can rapidly degrade many important Incretins, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), resulting in inadequate insulin secretion. Therefore, DPP-4 inhibitors can improve the activity of GLP-1 and GIP, promote insulin secretion, and lower blood sugar.
Clinical trials have shown that DPP-4 inhibitors can lower blood glucose levels and increase glucose tolerance, and there is no side effect, such as weight gain and hypoglycemia. At present, clinically applied DPP-4 inhibitors are Sitagliptin, Saxagliptin, Vildagliptin, Alogliptin and Linagliptin (Havale, S. H.; Pal, M. Bioorg. Med. Chem. 2009, 17, 1783-1802; Gupta, R.; Walunj, S. S.; Tokala, R. K.; Parsa, K. V.; Singh, S. K.; Pal, M. Curr. Drug. Targets, 2009, 10, 71-87). The market for hypoglycemic drugs is already dominated by hypoglycemic drugs as DPP-4 inhibitor. For example, in 2009, the sale of Sitagliptine from Merck & Co., Inc., reached $13.1 billion, which the only hypoglycemic drug which exceeded $10 billion.
However, all of the currently marketed DPP-4 inhibitors are in patent protection period, a variety of new DPP-4 inhibitors are still in clinical research stage. Therefore, there is an urgent need in the art for the development of novel, efficient DPP-4 inhibitors with low toxicity.